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Shape and dimension of the preferred nucleotide repeats in nucleic acids are found to depend on whether the sugar-phosphate linkage is of 2',5' or 3',5' type. It is shown that a nucleotide which is "compact" in 3',5' nucleic acids is rendered "extended" and vice versa for a given sugar pucker. It is interesting that this feature is accompanied by a switch in the preferred sugar ring conformation in 3',5' and 2',5' nucleic acids. 3' ribose and 3' deoxyribose rings (in 2',5' linkages) tend to favour C2' endo and C3' endo puckers respectively in contrast to C3' endo and C2' endo puckers favored by 2' ribose and 2' deoxyribose sugars (in 3',5' linkages). The distinguishable features between the nucleotide repeats of 3',5' and 2',5' nucleic acids need to be recognised while discussing their structural properties, as well as those of a variety of complexes that could be formed involving 2',5' and 3',5' strands of DNA and RNA. Ability and stability, or lack of them, for formation of a specific combination of these complexes may be directly related to the stereochemical constraints imposed as a consequence of conformationally homogeneous or heterogeneous nature of the repeating nucleotides of the complexing chains. As a first step towards delineating stereochemical features that distinguish 2',5' nucleic acids from their naturally occurring isomer A and B type helices have been modelled using the new concept of "compact" and "extended" nucleotide repeat that seemingly unifies helix generation of both types of linkages. Helical models for 2',5' RNA with "dinucleotide" repeat based on the crystal structure of 2',5' ApU have also been obtained.

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The NMR structure of 2¢,5¢ d(GGGGCCCC) was determined to gain insights into the structural differences between 2¢,5¢-and 3¢,5¢-linked DNA duplexes that may be relevant in elucidating nature's choice of sugar-phosphate links to encode genetic information. The oligomer assumes a duplex with extended nucleotide repeats formed out of mostly N-type sugar puckers. With the exception of the 5¢-terminal guanine that assumes the syn glycosyl conformation, all other bases prefer the anti glycosyl conformation. Base pairs in the duplex exhibit slide ()1.96 Å ) and intermediate values for X-displacement ()3.23 Å ), as in ADNA, while their inclination to the helical axis is not prominent. Major and minor grooves display features intermediate to A and BDNA. The duplex structure of iso d(GGGGCCCC) may therefore be best characterized as a hybrid of A and BDNA. Importantly, the results confirm that even 3¢ deoxy 2¢,5¢ DNA supports duplex formation only in the presence of distinct slide ( ‡ )1.6 Å ) and X-displacement ( ‡ )2.5 Å ) for base pairs, and hence does not favor an ideal BDNA topology characterized by their near-zero values. Such restrictions on base pair movements in 2¢,5¢ DNA, which are clearly absent in 3¢,5¢ DNA, are expected to impose constraints on its ability for deformability of the kind observed in DNA during its compaction and interaction with proteins. It is therefore conceivable that selection pressure relating to the optimization of topological features might have been a factor in the rejection of 2¢,5¢ links in preference to 3¢,5¢ links.Keywords: structure of 2¢,5¢ DNA; evolution of 3¢,5¢ vs. 2¢,5¢ links in nucleic acids; AB hybrid structure; restrained base pair movements; topological restrictions in 2¢,5¢ DNA.Nature's selection of 3¢,5¢ linkages (instead of 2¢,5¢ linkages) in nucleic acids, to encode genetic information, is intriguing. The fact that 2¢,5¢ links are formed in abundance and serve as a template in nonenzymatic reactions suggest that they might have been the ancestors of the biotic 3¢,5¢ links, which could have evolved from a pool of 3¢,5¢ and 2¢,5¢ links [1]. Nucleic acids with 2¢,5¢ links satisfy one of the critical features required for the fidelity of replication, namely that they associate to form Watson and Crick base-paired duplex structures [2][3][4][5], although with weaker affinity than 3¢,5¢-linked DNA strands. However, detailed knowledge about stereochemistry, polymorphism and topological properties of 2¢,5¢ DNA duplexes, which may provide insights into the factors that determine nature's choice of sugar-phosphate links from a stereochemical perspective, is sparse [6][7][8][9]. In fact, there are only two reports of NMR structure determination -one on a 2¢,5¢ DNA fragment [10] and one on a 2¢,5¢ RNA fragment [11] -both of which suggest an A-type duplex structure with some stereochemical details that differ from genomic DNA and RNA duplexes. In this context, it is relevant to recognize the results from recent modeling studies on 2¢,5¢ nucleic acids, which suggest that 2¢,5¢ DNA can...